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* Department of Medical and Scientific Services, Quintiles, Inc., Research Triangle Park, North Carolina; Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina; Brown University School of Medicine, Providence, Rhode Island; || Department of Obstetrics and Gynaecology, McMaster University Medical Center, Hamilton, Ontario; and ¶ Division of Pharmaceutical Sciences, Pharmacology-Toxicology, Duquesne University, Pittsburgh, Pennsylvania
To whom requests for reprints should be addressed at 1 P.O. Box 13979, Quintiles, Inc., Research Triangle Park, NC 27709. E-mail: Claude.hughes{at}quintiles.com
In utero and lactational exposure to estrogenic agents has been shown to influence morphological and functional development of reproductive tissues. Thus, consumption of dietary phytoestrogens, such as isoflavones, during pregnancy and lactation could influence important periods of development, when the fetus and neonate are more sensitive to estrogen exposure. In this study, reproductive outcomes after developmental exposure to isoflavones were examined in Long-Evans rats maternally exposed to isoflavones via a commercial soy beverage or as the isolated isoflavone, genistein. Most reproductive endpoints examined at birth, weaning, and 2 months of age were not significantly modified in pups of either sex after lactational exposure to soy milk (provided to the dams in place of drinking water) from birth until weaning. However, soy milk exposure induced a significant increase in progesterone receptor (PR) in the uterine glandular epithelium of the 2-month-old pups. In pregnant dams treated with genistein (GEN; 15 mg/kg body weight) by gavage, from Gestational Day 14 through weaning, PR expression in the uterine glandular epithelium from 2-month-old GEN-treated females (postexposure) was also significantly increased. Diethylstilbesterol (DES) also stimulated uterine PR expression only in the glandular but not luminal epithelial cells. However, unlike DES, in utero/lactational exposure to GEN did not increase expression of the proliferation marker, proliferating cell nuclear antigen (PCNA), in the luminal epithelial cells of the 2-month-old rat uteri. These experiments demonstrate that developmental exposure to dietary isoflavones, at levels comparable to the ranges of human exposure, modify expression of the estrogen-regulated PR in the uterus of sexually mature rats weeks after exposure ended. Since the PR is essential for regulating key female reproductive processes, such as uterine proliferation, implantation, and maintenance of pregnancy, its increased expression suggests that soy phytoestrogen exposure during reproductive development may have long-term reproductive health consequences.
Key Words: diethylstilbestrol • genistein • sexual development • puberty • phytoestrogens
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